Dr. Scott Gottlieb, head of Food and Drug Administration (FDA), recently announced that the FDA will continue to vigorously promote the development of gene therapy, and issued six new guidelines. In today's article, WuXi AppTec will share details of the new guidelines with readers.

Once a theory, gene therapy has become a therapeutic reality for patients. It has the potential to treat and cure some intractable diseases.  The policy framework set by the FDA for how genetic products are developed, reviewed and reimbursed by regulators will help lay the groundwork for continued growth of this new market. Last year, we published a draft on regenerative medicine framework that outlined several ways to accelerate development, such as breakthrough therapy designation (BTD) and regenerative medicine advanced therapy (RMAT) designation, which might be applicable to development institutions engaged in gene therapy. Today, the FDA introduces a complementary framework for the development, review, and approval of gene therapy.

 
♦In the draft on regenerative medicine framework released in November 2017, the FDA mentioned five ways to accelerate the approval of regenerative medicine products (Photo source: FDA website).

In the past 12 months, the FDA has approved three gene therapy products. This reflects the rapid development of the field. We have reached a point where we can reliably deliver Gene Cassettes into the body, cells and human bodies. In the future, we expect the field to continue to move forward, and many gene therapies for debilitating diseases are likely to be approved. These treatments have great potential. Our new initiatives are aimed at promoting the development of this innovative sector.

♦Three FDA-approved gene therapies (Source: FDA website)

Gene therapy is being studied for many diseases, including genetic diseases, autoimmune diseases, heart disease, cancer and AIDS. We look forward to working with the academic and research communities to provide safe and effective products for more patients. But we know that we still need to understand how genetic products work, how to use them safely, and whether they can continue to work in the body without long-term side effects. The more challenging aspects of gene therapy review than that of traditional drugs lie in manufacturing and quality, or we can call it efficacy duration. These cannot be fully answered in pre-market trials of any reasonable size. When approving some genetic products, we may need to accept some degree of uncertainty about these issues. For example, in some cases, it is not clear at the time of approval whether the therapy will be effective for a long time. The effective and reliable instrument to trace the therapy launched in the market, such as the post-marketing clinical trials, will become the key to advancing the field of gene therapy, and helping ensure that safe and innovative treatments will be created.

Even though there may be uncertainties, we need to ensure patient safety and adequately describe the potential risks of genetic products and demonstrate their benefits. Genetic products were originally employed to treat devastating diseases, many of which lack treatment, including some fatal ones. The FDA has always been willing to accept more uncertainty in the absence of available therapies in order to get promising treatments in time. In such case, the party applying for drug approval often needs to conduct post-marketing clinical trials, called phase IV trial, to confirm the clinical benefits of the drug. That's the privilege the Congress grants the FDA, for example, to expedite the approval.

When it comes to new technologies such as gene therapy, the FDA will keep pace to ensure that it can adapt to the unique challenges posed by these new technology platforms. Today, we are taking a step toward shaping the regulatory structure of modern gene therapy. The FDA projects to release a series of six scientific guidance documents that will serve as the cornerstone of a comprehensive regulatory framework to help us advance the gene therapy while ensure that new products meet the FDA's gold standard for safety and effectiveness.

Three draft guidance for gene therapy aiming at specific diseases

Today, we released three new drafts for the development of gene therapy products for specific diseases. These are the first three FDA drafts of gene therapy products for specific diseases.

Human gene therapy for hemophilia: gene therapy products hemophilia currently being developed as a single treatment will enable patients to develop absent or abnormal coagulation factors in the body for a long time, thus reducing or eliminating the need for coagulation factor substitutes. To determine the right path to develop these products, the FDA released the Draft Guidance on Gene Therapy Products that are Targeted to the Treatment of Hemophilia. Once finalized, this new guideline will provide recommendations on clinical trial design and pre-clinical considerations to support the development of these gene therapy products. In addition, the draft also provides suggestions on surrogate endpoints to accelerate the approval of gene therapy products for hemophilia.

Human gene therapy for retinal disorders: another trend is gene therapy products for retinal diseases. The FDA also plans to publish the Human Gene Therapy for Retinal Disorders Guidance. Gene therapy products currently in clinical trials for retinal disorders in the United States are usually given intravitreal or subretinal injections. In some cases, gene therapy products are packaged in devices to be implanted in the eyes. The new guidelines will focus on the specific issues of gene therapy for retinal diseases and provide recommendations for product development, pre-clinical testing and clinical trial design.

Gene therapy for rare diseases: diseases that affect fewer than 200,000 people in the United States are called rare diseases. According to the National Institutes of Health (NIH), nearly 7,000 rare diseases affect more than 25 million Americans. About 80% rare diseases are caused by single-gene defect, and about half affect children. Because most rare diseases have no approved treatment, there is significant unmet demand. One the Human Gene Therapy for Rare Diseases Guidance is finalized, it will provide recommendations on pre-clinical, manufacturing and clinical trial design. This message aims to help applicants design clinical development plans where there may be potential feasibility and safety issues with limited study groups, as well as issues with interpretive validity.

Update information of three draft guidance for gene therapy production

Here, we also provide a comprehensive update information of three existing draft guidance that addresses manufacturing issues related to gene therapy.

The first guidance is the Human Gene Therapy Investigational New Drugs (INDs) Chemistry, Manufacturing and Control Information (CMC). It specifies recommendations on how the applicant may provide sufficient CMC information to ensure the safety, uniformity, quality, purity and efficacy of gene-therapy products under research. The guidance applies to human gene therapy and to the use of products containing human gene therapy in combination with drugs or medical devices.

The second guidance Test Retrovirus with Replication Ability of Retrovirus Vector Gene Therapy Products during Product Manufacturing and Patient Follow-up provides additional recommendations to accurately test the respiratory control ratio (RCR) during the manufacturing of retrovirus-vector based gene therapy products and follow-up of patients who receive such products. Specifically, the guidance recommends identifying materials and quantities to be tested. The guidance also provides advice on general testing methods.

The third guidance Long-term Follow-up (LTFU) after Administration of Human Gene Therapy Products provides recommendations for designing LTFU observational studies to collect data on delayed adverse reaction after administration of gene therapy products. Due to the additional inherent uncertainties in new technology platforms such as gene therapy, including issues related to the durability of therapeutic effects and the theoretical off-target effects of incorrect gene insertion, it is necessary to conduct intensive LTFU of patients after such product is launched in the market. This guidance describes product characteristics, patient-related factors, pre-clinical and clinical data that should be considered in assessing the need for LTFU, and introduces the characteristics of effective post-marketing follow-up.

Once finalized, the draft guidance will replace earlier FDA guidance issued in April 2008 (CMC) and November 2006 (RCR and LTFU).

Gene therapy holds the promise of efficient treatment and even a cure for many treatment-resistant diseases. Some of these genetic products will almost certainly alter the paradigm of medical practice and the fate of patients with certain diseases.

The goal of the FDA is to help these innovative therapies develop within a framework that ensures safety and effectiveness and keep building the public's confidence in this emerging field of medicine.

References:
[1] STATEMENT FROM FDA COMMISSIONER SCOTT GOTTLIEB, M.D. ON AGENCY’S EFFORTS TO ADVANCE DEVELOPMENT OF GENE THERAPIES
[2] FDA website